P-047: PROSPECTIVE IDENTIFICATION OF VARIABLES AS OUTCOMES FOR TREATMENT (PIVOT): A PHASE II CLINICAL TRIAL OF HYDROXYUREA FOR CHILDREN AND ADULTS WITH HBSC DISEASE
Authors: SMART L., SEGBEFIA C., LATHAM T., STUBER S., AMISSAH-ARTHUR K., LANE A., DEI-ADOMAKOH Y., WARE R.
Journal: HemaSphere (2022)

Purpose: A substantial number of patients with sickle cell disease (SCD) have HbSC disease, especially those living in West Africa. HbSC may cause less early morbidity and mortality than sickle cell anemia (HbSS/Sβ0), but individuals with HbSC disease suffer from the same complications and have reduced quality of life. Retrospective data suggest some benefits of hydroxyurea treatment for people living with HbSC disease, but rigorous prospective evidence is lacking regarding the optimal dose, the effects on clinical and laboratory parameters, the safety of long-term treatment, and the best study endpoints to consider for a definitive Phase III trial of hydroxyurea therapy for HbSC disease. Therefore, we designed a clinical trial to achieve the following aims: 1) to measure the toxicities of hydroxyurea treatment on laboratory parameters; 2) to assess the effects of hydroxyurea treatment on a variety of sickle-related clinical and laboratory parameters in a large cohort of children and adults with HbSC disease; and 3) to identify study endpoints that are suitable for a future Phase III trial of patients with HbSC disease receiving hydroxyurea therapy. Materials and methods: Prospective Identification of Variables as Outcomes for Treatment (PIVOT) is a double-blinded, randomized, placebo-controlled phase II trial of hydroxyurea. Children and adults with HbSC disease, ages 5 to 50 years, and receiving care at Korle Bu Teaching Hospital in Accra, Ghana will be eligible. Participants will undergo initial screening for 2 months and then will be randomized to placebo or hydroxyurea (donated by Addmedica, Inc, Paris) with approximately 120 participants in each arm. Randomization will be stratified by age and sex to ensure that an equal number of children and adults with balanced baseline characteristics are enrolled in each arm. Results: Participants will first be treated with hydroxyurea or placebo for 12 months. Hydroxyurea will be prescribed initially at 20±5 mg/kg/day with an opportunity to escalate the dose twice over the first 6 months if appropriate laboratory parameters are met. If safety of hydroxyurea is confirmed, participants will be able to continue in a subsequent open label treatment phase for up to 48 months. Laboratory safety measures will include assessment of treatment-related cytopenias and change in whole blood viscosity. Primary outcomes of clinical efficacy will be the rate of SCD-related acute complications, and secondary outcomes will include change in hemoglobin and change in chronic organ function with measurement of intracranial arterial blood flow by transcranial Doppler ultrasound, near infrared spectrometry for oxygen utilization, spleen size and function by ultrasonography, renal assessment of proteinuria and kidney volume, and retinal imaging to assess for damage. Exploratory outcomes will include change in functional RBC analysis using a Laser Optical Rotational Red Cell Analyzer (Lorrca) and change in patient reported outcomes using the PROMIS questionnaire and 6-minute walk test. Conclusion: PIVOT is scheduled to begin enrollment by May 2022. For children and adults with HbSC disease PIVOT will determine the safety of hydroxyurea and identify measurable changes in a variety of laboratory and clinical parameters, suitable for future prospective testing in a definitive Phase III clinical trial.The authors do not declare any conflict of interest